Abstract
The history of modern oncology started around eighty years ago with the introduction of cytotoxic agents such as nitrogen mustard into the clinic, followed by multi-agent chemotherapy protocols. Early success in radiation therapy in Hodgkin lymphoma gave birth to the introduction of radiation therapy into different cancer treatment protocols. Along with better understanding of cancer biology, we developed drugs targeting cancer-related cellular and genetic aberrancies. Discovery of the crucial role of vasculature in maintenance, survival, and growth of a tumor opened the way to the development of anti-angiogenic agents. A better understanding of T-cell regulatory pathways advanced immunotherapy. Awareness of stem-like cancer cells and their role in cancer metastasis and local recurrence led to the development of drugs targeting them. At the same time, sequential and rapidly accelerating advances in imaging and surgical technology have markedly increased our ability to safely remove ≥90% of tumor cells. While we have advanced our ability to kill cells from multiple directions, we have still failed to stop most types of cancer from recurring. Here we analyze the tactics employed in cancer evolution; namely, chromosomal instability (CIN), intra-tumoral heterogeneity (ITH), and cancer-specific metabolism. These tactics govern the resistance to current cancer therapeutics. It is time to focus on maximally delaying the time to recurrence, with drugs that target these fundamental tactics of cancer evolution. Understanding the control of CIN and the optimal state of ITH as the most important tactics in cancer evolution could facilitate the development of improved cancer therapeutic strategies designed to transform cancer into a manageable chronic disease.
Highlights
The history of modern oncology started around eighty years ago with the introduction of cytotoxic agents such as nitrogen mustard into the clinic, followed by multi-agent chemotherapy protocols
chromosomal instability (CIN) and the optimal state of intra-tumoral heterogeneity (ITH) as the most important tactics in cancer evolution could facilitate the development of improved cancer therapeutic strategies designed to transform cancer into a manageable chronic disease
The rate of mutational processes and chromosomal instability is affected by constant variations and increase in these changes over time, and following chemotherapy, or radiation therapy, which act as geno-toxic agents [112]
Summary
One could historically consider the birth of the modern era of cancer therapeutics to be the serendipitous discovery of nitrogen mustard during the second world war [1]. As of today, almost 50 years after that date, different platinum derivatives are the cornerstone of head and neck, lung, and gynecological cancer treatment protocols [15]. Another contribution of platinum discovery was a wake-up call that, perhaps there are other platinum-like agents for other cancers that we have not yet tried. Discovery of the potential synergistic effects of radiation therapy and chemotherapy, together, generated a foundation that led to the combination of chemo and radiation therapy in the treatment of head and neck, lung, and brain cancer, as well as lymphoma treatment protocols [17,18,19]. Environmental factors, cancer prevention, screening, and early detection, followed in the footsteps of the above mentioned findings, and contribute to our present national health and cancer treatment policy guidelines
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